Chemical compounds

ABSTRACT

The present invention discloses compounds of Formula I. The present invention also discloses beta-3 agonists of formula I and methods for treating beta-3 mediated diseases and condition using the compounds of formula I, in particular methods for treating diabetes or obesity.

FIELD OF TH INVENTION

[0001] This invention relates to a new class of chemical compounds andto their use in medicine. In particular, the invention concerns novelphenethanolamine derivatives, methods for their preparation,pharmaceutical compositions containing them and their use as agonists ata typical beta-adrenoceptors (also known as beta-3-adrenoceptors).

BACKGROUND OF THE INVENTION

[0002] A typical beta-adrenoceptors belong to the family ofadrenoceptors that mediate the physiological actions of the hormonesadrenaline and noradrenaline. Such receptors have been described forexample by J R S Arch et. al., Nature, 309, 163-165 (1984); C Wilson et.al., Eur. J. Pharmacol., 100, 309-319 (1984); L J Emorine et. al.,Science, 245, 1118-1121 (1989); and A. Bianchetti et. al. Br. J.Pharmacol., 100, 831-839 (1990).

[0003] Phenethanolamine derivatives having activity at a typicalbeta-adrenoceptors are disclosed in, for example, European PatentApplications EP-A-0455006 and EP-A-0543662.

[0004] Sub-types of the adrenoceptors, α₁-, α₂-, β₁-, β₂- and β₃-(atypical) can be identified on the basis of their pharmacologicalproperties and physiological effects. Chemical agents that stimulate orblock these receptors (but not 3) are widely used in clinical medicine.More recently, emphasis has been placed upon specific receptorselectivity in order to reduce side effects caused, in part, byinteractions with other receptors.

[0005] Atypical beta-adrenoceptors are known to occur in adipose tissueand the gastrointestinal tract. Atypical beta-adrenoceptor agonists havebeen found to be particularly useful as thermogenic anti-obesity agentsand as anti-diabetic agents. Compounds having a typicalbeta-adrenoceptor agonist activity have also been described as beinguseful in the treatment of hyperglycaemia, as animal growth promoters,as blood platelet aggregation inhibitors, as positive inotropic agentsand as antiatherosclerotic agents, and as being useful in the treatmentof glaucoma.

SUMMARY OF THE INVENTION

[0006] The invention therefore provides, in a first aspect, compounds offormula I) and pharmaceutically acceptable derivatives thereof:

[0007] wherein X is oxygen or sulfur, optionally substituted by one ormore groups selected from C₁₋₄ alkyl and halogen, and where theheterocycle containing X is substituted meta or para to the depicted NH;

[0008] R¹ is hydrogen or C₁₋₆alkyl;

[0009] R represents substituents selected from C₁₋₆ alkyl, halogen,trifluoromethyl and C₁₋₆alkoxy; and

[0010] n represents an integer from 0-4.

[0011] Preferably the compounds of this invention are agonists for humanbeta-3 adrenoceptor (“β₃”). More preferably, the compounds of thisinvention are selective agonists for β₃.

[0012] In another aspect, the present invention provides apharmaceutical formulation comprising a compound of the invention.Preferred pharmaceutical compositions further comprise apharmaceutically acceptable carrier.

[0013] In another aspect, the present invention provides a method forthe prevention or treatment of clinical conditions or diseasessusceptible to amelioration by administration of an a typicalbeta-adrenoceptor agonist, comprising administration of an effectiveamount of a compound or composition of this invention.

[0014] In a further aspect, the present invention provides the use of acompound of formula (I), or a pharmaceutically acceptable derivativethereof, in the manufacture of a medicament for the treatment ofconditions or diseases susceptible to amelioration by administration ofan a typical beta-adrenoceptor agonist.

DETAILED DESCRIPTION OF THE INVENTION

[0015] As used herein, the terms ‘alkyl’ and “alkoxy” mean a straight orbranched alkyl group or alkoxy group respectively, containing theindicated number of carbon atoms. For example, C₁₋₆alkyl means astraight or branched alkyl containing at least 1 and at most 6 carbonatoms.

[0016] Preferably the heterocycle containing X is substituted meta tothe depicted NH.

[0017] Preferably R¹ is hydrogen or methyl. When R¹ is other thanhydrogen, then preferably the stereochemisty around the carbon to whichR¹ is bonded is R.

[0018] Preferably R is chlorine, fluorine, or CF₃.

[0019] Preferably n is 0, 1, or 2. Most preferably n is 0.

[0020] Preferably the stereochemisty around the carbon to which thedepicted OH is bonded is R.

[0021] It will be appreciated that the above compounds of Formula (I)may contain optically active centers. The individual, isolated isomersand mixtures thereof, including racemates, are all within the scope ofthe present invention. Typically, where R¹ is methyl, mixtures ofdiastereomers of compounds of Formula (I) may be obtained, which areenriched with greater than or equal to 80% by weight of onediastereomer.

[0022] Suitable compounds of formula (I) of the invention include:

[0023]2-(3-{2R-[2-(3-Chlorophenyl)-2R-hydroxyl-ethylamino]propylamino}phenyl)furan-3-carboxylicacid;

[0024]2-(3-{[2-(3-Chlorophenyl)-2R-hydroxyl-ethylamino]ethylamino}phenyl)furan-3-carboxylicacid;

[0025]2-(4-{2R-[2-(3-Chlorophenyl)-2R-hydroxyl-ethylamino]propylamino}phenyl)furan-3-carboxylicacid;

[0026]2-(3-{2R-[2-(3-Chlorophenyl)-2R-hydroxyl-ethylamino]propylamino}phenyl)thiophene-3-carboxylicacid;

[0027]2-(3-{[2-(3-Chlorophenyl)-2R-hydroxyl-ethylamino]ethylamino}phenyl)thiophene-3-carboxylicacid;

[0028]2-(4-{2R-[2-(3-Chlorophenyl)-2R-hydroxyl-ethylamino]propylamino}phenyl)thiophene-3-carboxylicacid; and pharmaceutically acceptable derivatives thereof.

[0029] Particularly preferred compounds of the invention include:

[0030]2-(3-{[2-(3-Chlorophenyl)-2R-hydroxyl-ethylamino]ethylamino}phenyl)furan-3-carboxylicacid;

[0031]2-(3-{[2-(3-Chlorophenyl)-2R-hydroxyl-ethylamino]ethylamino}phenyl)thiophene-3-carboxylicacid; and pharmaceutically acceptable derivatives thereof.

[0032] By “a pharmaceutically acceptable derivative” is meant anypharmaceutically acceptable salt, ester, or salt of such ester, of acompound of formula (I) or any other compound which, upon administrationto the recipient, is capable of providing (directly or indirectly) acompound of formula (I) or an active metabolite or residue thereof.

[0033] It will be appreciated by those skilled in the art that thecompounds of formula (I) may be modified to provide pharmaceuticallyacceptable derivatives thereof at any of the functional groups in thecompounds of formula (I). Of particular interest as such derivatives arecompounds modified at the carboxyl function, hydroxyl functions or atamino groups.

[0034] It will be appreciated by those skilled in the art that thepharmaceutically acceptable derivatives of the compounds of formula (I)may be derivatised at more than one position.

[0035] Preferred pharmaceutically acceptable derivatives of thecompounds of formula (I) are pharmaceutically acceptable salts thereof.

[0036] Pharmaceutically acceptable salts of the compounds of formula (I)include those derived from pharmaceutically acceptable inorganic andorganic acids and bases. Examples of suitable acids includehydrochloric, hydrobromic, sulphuric, nitric, perchloric, fumaric,maleic, phosphoric, glycollic, lactic, salicylic, succinic,toluene-p-sulphonic, tartaric, acetic, citric, methanesulphonic, formic,benzoic, malonic, naphthalene-2-sulphonic and benzenesulphonic acids.Other acids such as oxalic, while not in themselves pharmaceuticallyacceptable may be useful in the preparation of salts useful asintermediates in obtaining compounds of the invention and theirpharmaceutically acceptable acid addition salts.

[0037] Salts derived from appropriate bases include alkali metal (e.g.sodium), alkaline earth metal (e.g. magnesium), ammonium and NR4+(whereR is C₁₋₄alkyl) salts.

[0038] The compounds of formula (I) and their pharmaceuticallyacceptable derivatives act as agonists at a typical beta-adrenoceptorsand as such are useful in the treatment of clinical conditionssusceptible to amelioration by administration of an a typicalbeta-adrenoceptor agonist. Such conditions include hyperglycaemia,obesity, hyperlipemia, irritable bowel syndrome and its associated pain,motility dysfunction, excessive gastrointestinal secretion, non-specificdiarrhoea, neurogenic inflammation, regulation of intraocular pressure,triglyceridemia, diabetes, e.g. non-insulin-dependent diabetes mellitus(NIDDM or Type 2), such as obese NIDDM and non-obese NIDDM, diabeticcomplications such as retinopathy, nephropathy, neuropathy, cataracts,coronary heart diseases and arteriosclerosis, osteoporosis; andgastrointestinal disorders, particularly inflammatory gastrointestinaldisorders. They are also of use in increasing thehigh-density-lipoprotein (HDL) cholesterol concentration and decreasingthe triglyceride concentration in blood serum, especially human bloodserum, and are therefore of potential use in the treatment and/orprophylaxis of atherosclerosis. They also may be useful for thetreatment of hyperinsulinaemia, depression, muscle wasting, and urinaryincontinence. References in this specification to treatment includeprophylactic treatment as well as the alleviation of symptoms.

[0039] In a further aspect, the invention provides the use of a compoundof general Formula (I) or a pharmaceutically acceptable salt or solvatethereof, for the manufacture of a medicament for the treatment of acondition susceptible of amelioration by an a typical beta-adrenoceptoragonist.

[0040] While it is possible that, for use in therapy, a compound of theinvention may be administered as the raw chemical it is preferable topresent the active ingredient as a pharmaceutical formulation. Theinvention thus further provides a pharmaceutical formulation comprisinga compound of Formula (I) or a pharmaceutically acceptable derivativethereof together with one or more pharmaceutically acceptable carriersthereof and, optionally, other therapeutic and/or prophylacticingredients. The carrier(s) or excipient(s) must be “acceptable” in thesense of being compatible with the other ingredients of the formulationand not deleterious to the recipient thereof.

[0041] The compounds for use according to the present invention may beformulated for oral, buccal, parenteral, rectal or transdermaladministration or in a form suitable for administration by inhalation orinsulation (either through the mouth or the nose).

[0042] For oral administration, the pharmaceutical compositions may takethe form of, for example, tablets or capsules prepared by conventionalmeans with pharmaceutically acceptable excipients such as binding agents(e.g. pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropylmethylcellulose); fillers (e.g. lactose, microcrystalline cellulose orcalcium hydrogen phosphate); lubricants (e.g. magnesium stearate, talcor silica); disintegrants (e.g. potato starch or sodium starchglycollate); or wetting agents (e.g. sodium lauryl sulphate). Thetablets may be coated by methods well known in the art. Liquidpreparations for oral administration may take the form of, for example,solutions, syrups or suspensions, or they may be presented as a dryproduct for constitution with water or other suitable vehicle beforeuse. Such liquid preparations may be prepared by conventional means withpharmaceutically acceptable additives such as suspending agents (e.g.sorbitol syrup, cellulose derivatives or hydrogenated edible fats);emulsifying agents (e.g. lecithin or acacia); non-aqueous vehicles (e.g.almond oil, oily esters, ethyl alcohol or fractionated vegetable oils);and preservatives (e.g. methyl or propyl-p-hydroxybenzoates or sorbicacid). The preparations may also contain buffer salts, flavoring,coloring and sweetening agents as appropriate. Preparations for oraladministration may be suitably formulated to give controlled release ofthe active compound.

[0043] For buccal administration the compositions may take the form oftablets or lozenges formulated in conventional manner.

[0044] The compounds according to the present invention may beformulated for parenteral administration by injection e.g. by bolusinjection or continuous infusion. Formulations for injection may bepresented in unit dosage form e.g. in ampoules or in multi-dosecontainers, with an added preservative. The compositions may take suchforms as suspensions, solutions or emulsions in oily or aqueousvehicles, and may contain formulatory agents such as suspending,stabilizing and/or dispersing agents. Alternatively, the activeingredient may be in powder form for constitution with a suitablevehicle, e.g. sterile pyrogen-free water, before use.

[0045] The compounds according to the present invention may also beformulated in rectal compositions such as suppositories or retentionenemas, e.g. containing conventional suppository bases such as cocoabutter or other glycerides.

[0046] In addition to the formulations described previously, thecompounds may also be formulated as a depot preparation. Such longacting formulations may be administered by implantation (for examplesubcutaneously, transcutaneously or intramuscularly) or by intramuscularinjection. Thus, for example, the compounds according to the presentinvention may be formulated with suitable polymeric or hydrophobicmaterials (for example as an emulsion in an acceptable oil) or ionexchange resins, or as sparingly soluble derivatives, for example, as asparingly soluble salt.

[0047] Suitable therapeutic ingredients which may be formulated withcompounds of the invention, together with one or more pharmaceuticalcarriers or excipients, include ingredients which may be used in thesame clinical conditions as those listed herein for atypicalbeta-adrenoceptor agonists. Such ingredients may include, for example,PPAR-gamma agonists.

[0048] A proposed dose of the compounds according to the presentinvention for administration to a human (of approximately 70 kg bodyweight) is 0.1 mg to 1 g, preferably to 1 mg to 100 mg of the activeingredient per unit dose, expressed as the weight of free base. The unitdose may be administered, for example, 1 to 4 times per day. The dosewill depend on the route of administration. It will be appreciated thatit may be necessary to make routine variations to the dosage dependingon the age and weight of the patient as well as the severity of thecondition to be treated. The precise dose and route of administrationwill ultimately be at the discretion of the attendant physician orveterinarian.

[0049] The compounds of the invention may be prepared by any of theprocesses known in the art for the preparation of similar compounds. Forexample, according to a first process wherein X, R¹, and R are asdefined as for formula (I), compounds of formula (I) may be prepared byreaction of compounds of formula

[0050] (II) and (III)

[0051] where P¹ and P² are suitable protecting groups for oxygen andnitrogen groups respectively and R² is lower alkyl or H, in the presenceof a reducing agent, followed by deprotection of any protecting groupspresent.

[0052] Compounds of formula (II) are described in PCT publication numberWO95/33724 or may be prepared by standard methods.

[0053] In an alternative process, a compound of formula (I) may beprepared by hydrolysis of a compound of formula (IV) or apharmaceutically acceptable version thereof:

[0054] wherein R and R¹ are as defined in formulas (II) and (III), R² islower alkyl and R³ represents C₁₋₆ alkyl or aryl optionally substitutedby hydrogen, C₁₋₆ alkyl or halogen; followed by the step of hydrolysingthe ester group —CO₂R² to produce a compound of formula (I), wherein thefuran ring is substituted by a —CO₂H group.

[0055] Preferably, hydrolysis of a compound of formula (IV) to form acompound of Formula (I) is carried out by reflux in the presence of anaqueous solution of a group 1 or group 2 metal hydroxide, e.g. NaOH orKOH, and preferably an alkanol, e.g. MeOH, for at least 4 h. The step ofhydrolysing the ester group —CO₂R² to produce a compound of formula(IA), wherein R⁴ is substituted by a —CO₂H group can be carried out by afurther hydrolysis step under standard hydrolysis conditions as would beapparent to a skilled person.

[0056] A compound of formula (IV) may be prepared by reacting a compoundof formula (V) with a compound of formula (VI):

[0057] at elevated temperature and pressure, optionally in the presenceof one or more of: C₃₋₆alkanols, acetonitrile, N-methyl-pyrrolidinone(NMP), isobutylacetate, isopropylacetate, dimethylformamide (DMF),toluene, xylene or dimethylacetamide (DMA); preferably toluene and/orxylene. The temperature for the reaction is suitably 100° C. or greater,preferably 100-150° C., more preferably 100-120° C.

[0058] The reaction of a compound of formula (V) with a compound offormula (VI) to form a compound of formula (IV) and the subsequentconversion of a compound of formula (IV) to a compound of formula (I)may be carried out separately or in situ. The reaction is preferablycarried out in situ.

[0059] A compound of formula (VI) may be prepared from a compound offormula (VII):

[0060] wherein L represents a leaving group such as a halogen atom (e.g.chlorine), by cyclisation in the presence of a solvent selected from:dichloromethane (DCM), EtOAc, toluene and/or xylene, and a base selectedfrom: Na₂CO₃, NaOH, anhydrous Et₃N and/or an amine, e.g. aqueous NH₃.Preferably the solvent is DCM. Preferably the base is aqueous NH₃.

[0061] Compounds of Formula (VII) may be prepared from compounds ofFormula (III) using any suitable method for the preparation of amidines.For example, by condensation of a compound of Formula (VIII) wherein Lrepresents

[0062] a leaving group

[0063] as previously defined, in the presence of a solvent selectedfrom: DCM, toluene, EtOAc, or CH₃CN, and PCl₅ or POCl₃. Preferably thesolvent is EtOAc. Preferably PCl₅ is present.

[0064] A compound of formula (III) may be prepared by reaction of acompound of formula (IX)

[0065] where Y represents the diazonium salt N₂ ⁺, with a suitable5-membered heterocyclic ring of formula (X), followed by reduction ofthe nitro group using standard methods. Suitable compounds of formula(X) are known or are prepared by standard methods. For example, where Xis oxygen, thus forming a furan group, a compound of formula (III) maybe prepared directly by reaction of a compound of formula (IX) where Yrepresents the diazonium salt N₂ ⁺ with a furan of formula (X), followedby reduction with standard methods. A compound of formula (IX) where Yrepresents the diazonium salt N₂+may in turn be prepared from a compoundof formula (IX) where Y═NH₂ by standard methods known in the literature.Alternatively, a compound of formula (III) may be prepared from thereaction of a compound of formula (IX) where Y=Br, I or triflate with afuran of formula (X) in the presence of a suitable palladium catalystand a suitable base followed by reduction of the nitro group understandard conditions. Suitable palladium catalysts include, but are notlimited to, tetrakis(triphenylphosphine)palladium(0). Suitable basesinclude, but are not limited to KOAc. Use of the palladium catalystPd(PPh₃)₄ in the presence of the base KOAc is preferred.

[0066] Compounds of formula (IX) are known compounds or may be preparedby processes well known in the art.

[0067] Suitable reducing agents of use in the reactions include hydrogenin the presence of a catalyst, such as a noble metal catalyst, forexample palladium, platinum or platinum oxide, Raney-nickel or hydridereducing agents such as borohydrides, for example sodium borohydridesodium triacetoxyborohydride or sodium cyanoborohydride. Suitablereaction conditions will be readily apparent to those skilled in the artand are further illustrated by the accompanying examples.

[0068] The protecting groups used in the preparation of compounds offormula (I) may be used in conventional manner. See for example‘Protective Groups in Organic Chemistry’ Ed. J. F. W. McOmie (PlenumPress 1973) or ‘Protective Groups in Organic Synthesis’ by Theodora WGreene and P M G Wuts (John Wiley and Sons 1991).

[0069] Conventional amino protecting groups may include for examplearalkyl groups, such as benzyl, diphenylmethyl or triphenylmethylgroups; and acyl groups such as N-benzyloxycarbonyl or t-butoxycarbonyl.

[0070] Conventional oxygen protecting groups may include for examplealky silyl groups, such as trimethylsilyl, or tert-butyidimethylsilyl;alkyl ethers such as tetrahydropyranyl, or tert-butyl; or esters such asacetate.

[0071] Removal of any protecting groups present may be achieved byconventional procedures.

[0072] Atypical beta-adrenoceptor agonists are compounds, whichdemonstrate a pharmacological response mediated at atypicalbeta-adrenoceptors. This activity has been measured as the ability tostimulate lipolysis by rat adipocytes at sub-micromolar concentrations,in a response that is resistant to blockade by standardbeta-adrenoceptor blocking drugs such as propranolol.

[0073] Another useful means of identifying an a typicalbeta-adrenoceptor agonist involves the measurement of agonist activityat a typical beta-adrenoceptors in the rat isolated lower oesophagus.Typically in this assay, a compound of general Formula (I) for useaccording to the present invention has an equipotent molar ratio (EPMR)relevant to isoprenaline of less than 30. The rat oesophagus assay isbased upon that described by Ford et. al., Br. J. Pharmacol.,105(suppl.), 235P, 1992. The relative potency of each test compound(EPMR) is compared to isoprenaline as follows:${EPMR} = \frac{{EC50}\quad {agonist}}{{EC50}\quad {isoprenaline}}$

[0074] wherein EC₅₀ is the molar concentration of agonist which produces50% of the maximum possible response for that agonist.

[0075] A particularly useful method for determining agonist activity athuman a typical beta-adrenoceptors involves the use of Chinese hamsterovarian (CHO) cells transfected with the human beta-3-adrenoceptoraccording to Method 1. The cell lines may also be transfected with humanbeta-1- and beta-2-adrenoceptor in a similar manner to provide a methodof determining the selectivity of the compounds of the invention at thethree receptors.

[0076] Method 1—Cell Culture

[0077] General cell culture guidelines are observed (Fershney, R. A.(1987) Culture of animal cells: A manual of basic technique. Wiley-Liss,Inc., N.Y.). A standard cell culture incubator is used (37° C., 5% CO2in air, 95% relative humidity). H β₃CHO cells are grown in DMEM/FI2(with pyroxidine-HCl, 15 mM HEPES, L-glutamine), supplanted with 10%heat-inactivated FBS, 500 μg/ml G418, 2 mM L-glutamine, 100 unitspenicillin G and 100 μg streptomycin sulfate. One confluent flask ofcells is trypsinised and resuspended in the above medium at aconcentration of 30-40,000 cells/100 μl and plated into 96-well flatbottom plates. The cells are then used for assay within 18-24 hours.

[0078] The medium is aspirated from each well, and replaced with 180 μlDMEM/F12 with 500 mM IBMX. Antagonists, if required, are added at thisstage. The plate is then placed back in the incubator for 30 min. Drugsare then added to the wells (20 μl, 100× required final concentration)for 60 min. Responses were determined by measuring cAMP levels of a 20ul sample of extracellular media using a scintillation proximity basedradio-immunoassay (NEN Flashplates).

[0079] CHO-6CRE-luciferase cell lines which stably express hβ₃ receptorsare seeded at 30,000 cells/well for 24 hr in DMEM/F12 containing 10%FBS. Media is removed from the cells and replaced with DMEM/F12 buffer(180 μl) containing 300 mM IBMX and 1 mM ascorbic acid for 30 min priorto addition of compound. Vehicle or agonist (20 μl) is added andincubated at 37° C. for 60 minutes. At the end of the incubation period,samples of extracellular media are removed for direct assay in cAMPFlashplates (NEN).

[0080] As used herein, a compound is considered to be an agonist for hβ₃if the compound stimulates the accumulation of extracellular cAMP withCHO-6CRE-luciferase cells expressing hβ₃. The compounds of thisinvention have an EC₅₀ of at most 10 nM at hβ₃. The relative potency ofa h₃ agonist may be compared to its potency for stimulating theaccumulation of extracellular cAMP with CHO-6CRE-luciferase cellsexpressing hβ₂ and hβ₁. The compounds of this invention are at least 100times more potent at hβ₃ than at hβ₂ or hβ₁.

[0081] The invention is further illustrated by the followingintermediates and examples. All temperatures are in degrees centigrade.Chromatography was carried out on silica (Merck 9385) unless otherwisestated. HPLC characterization systems are labeled as follows:

[0082] System 1: (C18), using a 30-80% acetonitrile-water with 0.1%trifluoroacetic acid gradient mobile phase with detection by absorbanceat 254 nM.

[0083] System 2: (C18), using 1:4 acetonitrile-water containingtrifluoroacetic acid (0.1%) and triethylamine (0.1%) mobile phase withdetection by absorbance at 254 nM.

[0084] System 3: (C18), using 30-100% acetonitrile-water containingtrifluoroacetic acid (0.1%) and triethylamine (0.1%) mobile phase withdetection by absorbance at 254 nM.

[0085] System 4: (C18), using 1:1 acetonitrile-water containingtrifluoroacetic acid (0.1%) mobile phase with detection by absorbance at254 nM HPLC retention times are expressed in minutes as t_(R).

[0086] Intermediate 1

[0087]2-[3-(2R-{tert-Butoxycarbonyl-[2R-(tert-butyldimethylsilanoxy)-2-(3-chlorophenyl)ethyl]-amino}propylamino)phenyl]furan-3-carboxylicAcid Methyl Ester.

[0088] A solution of 2-(3-aminophenyl)furan-3-carboxylic acid methylester (0.31 g) and{2R-(tert-butoxycarbonyl)-[2R-(tert-butyldimethylsilanoxy)-2-(3-chlorophenyl)ethyl]amino}propionaldehyde(0.63 g) in dichloromethane (9 mL) containing acetic acid (0.03 mL) wasstirred at room temperature for 30 min. The reaction mixture was cooledto 0° C. and sodium triacetoxyborohydride (0.30 g) was added. Themixture was stirred at room temperature for 18 h, washed with aqueoussodium bicarbonate solution, dried over magnesium sulfate, andconcentrat d under reduced pressure. The residue was chromatographed onsilica eluting with hexanes: ethyl acetate (9:1) to give the titlecompound as a yellow solid (0.523 g). C₃₄H₄₇N₂O₆ClSi: M+Na 665

[0089] Similarly Prepared Were:

[0090] Intermediate 2

[0091]2-[3-{tert-Butoxycarbonyl-[2R-(tert-butyidimethylsilanoxy)-2-(3-chlorophenyl)ethyl]-amino}ethylamino)phenyl]furan-3-carboxylicacid methyl ester as a colorless gum (1.15 g), C₃₃H₄₅N₂O₆ClSi: MH⁺ 629,from 2-(3-aminophenyl)furan-3-carboxylic acid methyl ester (742 mg) and{(tert-butoxycarbonyl)-[2R-(tert-butyl-dimethyl-silanyloxy)-2-(3-chloro-phenyl)-ethyl]-amino}acetaldehyde(1.17 g).

[0092] Intermediate 3

[0093]2-[4-(2R-{tert-Butoxycarbonyl-[2R-(tert-butyldimethylsilanoxy)-2-(3-chlorophenyl)ethyl]-amino}propylamino)phenyl]furan-3-carboxylicacid methyl ester as a brown oil (0.45 g), TLC hexane:ethyl acetate(1:1) R_(f)=0.65, from 2-(4-aminophenyl)furan-3-carboxylic acid methylester (0.22 g) and{2R-(tert-butoxycarbonyl)-[2R-(tert-butyidimethylsilanoxy)-2-(3-chlorophenyl)ethyl]amino}propionaldehyde(0.45 g).

[0094] Intermediate 4

[0095]2-[3-(2R-{tert-Butoxycarbonyl-[2R-(tert-butyldimethylsilanoxy)-2-(3-chlorophenyl)ethyl]amino}propylamino)phenyl]thiophene-3-carboxylicacid methyl ester as a yellow oil (0.383 g), TLC hexane:ethyl acetate(1:1) R_(f)=0.66, from 2-(3-aminophenyl)thiophene-3-carboxylic acidmethyl ester (0.30 g) and {2R-(tert-butoxycarbonyl)-[2R-(tert-butyldimethylsilanoxy)-2-(3-chlorophenyl)ethyl]amino}propionaldehyde (0.56 g).

[0096] Intermediate 5

[0097]2-[3-{tert-Butoxycarbonyl-[2R-(tert-butyidimethylsilanoxy)-2-(3-chlorophenyl)ethyl]-amino}ethylamino)phenyl]thiophene-3-carboxylicacid methyl ester as a colorless gum (1.15 g). C₃₃H₄₅N₂O₅ClSSi: MH⁺ 646,from 2-(3-aminophenyl)thiophene-3-carboxylic acid methyl ester (795 mg)and{(tert-butoxycarbonyl)[2R-(tert-butyl-dimethyl-silanyloxy)-2-(3-chloro-phenyl)-ethyl]-amino}-acetaldehyde(1.17 g).

[0098] Intermediate 6

[0099]2-[4-(2R-{tert-Butoxycarbonyl-[2R-(tert-butyldimethylsilanoxy)2-(3-chlorophenyl)ethyl]amino}propylamino)phenyl]thiophene-3-carboxylicacid methyl ester as a yellow oil (0.155 g), C₃₄H₄₇N₂O₅ClSSi: MH⁺ 659,from 2-(4-aminophenyl)thiophene-3-carboxylic acid methyl ester (0.17 g)and{2R-(tert-butoxycarbonyl)-[2R-(tert-butyidimethylsilanoxy)-2-(3-chlorophenyl)ethyl]amino}propionaldehyde(0.32 g).

[0100] Intermediate 7

[0101] 2-(3-Nitrophenyl)furan-3-carboxylic Acid

[0102] A solution of 3-nitroaniline (8.28 g) in concentratedhydrochloric acid (20 mL) was treated with sodium nitrite (4.2 g) inwater (20 mL) at 0° C. The mixture was stirred for 10 min, and thenfiltered. To the filtrate was added 3-furancarboxylic acid (6.05 g) inacetone (10 mL), followed by a solution of cupric chloride (2.4 g) inwater (8 mL). The mixture was left to stand at room temperature for twodays, poured into water (200 mL), and stirred for two hours. Theresulting solid was dissolved in 10% sodium bicarbonate solution, andtriturated with ethyl aceate. The resulting aqueous solution wasacidified with 1N hydrochloric acid to precipitate a solid.Recrystallization of the solid from benzene gave the title compound as abrown solid (3.57 g). C₁₁H₇NO₅: MH⁺ 232

[0103] Similarly Prepared Were:

[0104] Intermediate 8

[0105] 2-(4-Nitrophenyl)furan-3-carboxylic acid as a tan solid (1.52 g),n.m.r. (DMSO-d₆) δ values include 6.91 (s, 1H),7.96 (s, 1H), 8.27 (dd,4H), 13.09 (bs, 1H), from 4-nitroaniline (4.14 g) and 3-furancarboxylicacid (3.03 g).

[0106] Intermediate 9

[0107] 2-(3-Nitrophenyl)thiophene-3-carboxylic acid as a tan solid (0.45g), C₁₁H₇NO₄S: MH⁻ 248, from 3-nitroaniline (4.14 g) and3-thiophenecarboxylic acid (3.46 g).

[0108] Intermediate 10

[0109] 2-(4-Nitrophenyl)thiophene-3-carboxylic acid as a tan solid (2.83g), is C₁₁H₇NO₄S: MH⁻ 248, from 4-nitroaniline (4.14 g) and3-thiophenecarboxylic acid (3.46 g).

[0110] Intermediate 11

[0111] 2-(3-Nitrophenyl)furan-3-carboxylic Acid Methyl Ester

[0112] A solution of 2-(3-nitrophenyl)furan-3-carboxylic acid (1.2 g) inmethanol (200 mL) containing concentrated sulfuric acid (5 drops) washeated under reflux for 18 h. The reaction solution was evaporated todryness under reduced pressure to give the title compound as a yellowsolid (0.66 g). m.p.=93-94° C.

[0113] Similarly Prepared Were:

[0114] Intermediate 12

[0115] 2-(4-Nitrophenyl)furan-3-carboxylic acid methyl ester as a yellowsolid (1.15 g), m.p.=113-114° C., from2-(4-nitrophenyl)furan-3-carboxylic acid (0.52 g).

[0116] Intermediate 13

[0117] 2-(3-Nitrophenyl)thiophene-3-carboxylic acid methyl ester as awhite solid (0.31 g),

[0118] C₁₂H₉NO₄S: MH⁻ 262, from 2-(3-nitrophenyl)thiophene-3-carboxylicacid (0.45 g).

[0119] Intermediate 14

[0120] 2-(4-Nitrophenyl)thiophene-3-carboxylic acid methyl ester as awhite solid (1.0 g), n.m.r. (DMSO-d₆) 8 values include 3.78 (s, 3H),7.43 (d, 1H), 7.64 (m, 1H), 7.72 (m, 2H), 8.21 (d, 1H), 8.33 (m, 1H),from 2-(4-nitrophenyl)thiophene-3-carboxylic acid (1.5 g).

[0121] Intermediate 15

[0122] 2-(3-Aminophenyl)furan-3-carboxylic Acid Methyl Ester

[0123] A solution of 2-(3-nitrophenyl)furan-3-carboxylic acid methylester (1.0 g) in methanol (60 mL) containing 10% palladium on carbon(2.9 g) was stirred under 1 atmosphere of hydrogen for 1 h. The reactionmixture was then filtered through Celite. Removal of the solvent atreduced pressure gave the title compound as a yellow solid (0.75 g).C₁₂H₁₁NO₃: M+Na+240

[0124] Similarly Prepared Were:

[0125] Intermediate 16

[0126] 2-(4-Aminophenyl)furan-3-carboxylic acid methyl ester as a yellowsolid (1.0 g), Assay Found: C 66.19; H 5.17; N 6.33%, C₁₂H₁₁NO₃ requiresC 66.35; H 5.10;

[0127] N 6.45%, from 2-(4-nitrophenyl)furan-3-carboxylic acid methylester (1.0 g).

[0128] Intermediate 17

[0129] 2-(3-Aminophenyl)thiophene-3-carboxylic acid methyl ester as abrown oil (0.30 g),

[0130] C₁₂H₁₁NO₂S: M+Na⁺ 255, from2-(3-nitrophenyl)thiophene-3-carboxylic acid methyl ester (0.30 g).

[0131] Intermediate 18

[0132] 2-(4-Aminophenyl)thiophene-3-carboxylic acid methyl ester as abrown oil (0.17 g),

[0133] C₁₂H₁₁NO₂S: MH⁺ 234, from 2-(4-nitrophenyl)thiophene-3-carboxylicacid methyl ester (0.70 g).

[0134] Intermediate 19

[0135]2-(3-{2R-[2-(3-Chlorophenyl)-2R-hydroxyl-ethylamino]propylamino}phenyl)furan-3-carboxylicAcid Methyl Ester

[0136]2-[3-(2R-{tert-Butoxycarbonyl-[2R-(tert-butyldimethylsilanoxy)-2-(3-chlorophenyl)ethyl]amino}propylamino)phenyl]furan-3-carboxylicacid methyl ester (0.523 g) was dissolved in 4N hydrochloric acid indioxane (5.0 mL), stirred at room temperature for 1 h and then dilutedwith diethyl ether (10 mL) to separate an oil. The oil waschromatographed on silica and eluting with ethyl acetate: methanol (9:1)to give the title compound as a red oil (0.19 g).

[0137] C₂₃H₂₅N₂O₄Cl: MH⁺ 429

[0138] Intermediate 20

[0139]2-(3-{2R-[2-(3-Chlorophenyl)-2R-hydroxyl-ethylamino]propylamino}phenyl)furan-3-carboxylicacid methyl ester hydrochloride as a white solid (613 mg), C₂₂H₂₃N₂O₄Cl:MH⁺ 415, from2-[3-{tert-butoxycarbonyl-[2R-(tert-butyldimethylsilanoxy)-2-(3-chlorophenyl)ethyl]-amino}ethylamino)phenyl]thiophene-3-carboxylicacid methyl ester (1.15 g).

[0140] Similarly Prepared Were:

[0141] Intermediate 21

[0142]2-(4-{2R-[2-(3-Chlorophenyl)-2R-hydroxyl-ethylamino]propylamino}phenyl)furan-3-carboxylicacid methyl ester as a brown oil (0.19 g), TLC ethyl acetate: methanol(8:2) R_(f)=0.27, from2-[4-(2R-{tert-butoxycarbonyl-[2R-(tert-butydimethylsilanoxy)-2-(3-chlorophenyl)ethyl]-amino}propylamino)phenyl]furan-3-carboxylicacid methyl ester (0.45 g).

[0143] Intermediate 22

[0144]2-(3-{2R-[2-(3-Chlorophenyl)-2R-hydroxyl-thylamino]propylamino}phenyl)thiophene-3-carboxylicacid methyl ester as an range oil (0.086 g), C₂₃H₂₅N₂O₃ClS: MH⁺ 445,from2-[3-(2R-{tert-utoxycarbonyl-[2R-(tert-butyidimethylsilanoxy)-2-(3-chlorophenyl)ethyl]amino}ropylamino)phenyl]thiophene-3-carboxylic acid methyl ester (0.383 g).

[0145] Intermediate 23

[0146]2-(3-{2R-[2-(3-Chlorophenyl)-2R-hydroxyl-thylamino]propylamino}phenyl)thiophene-3-carboxylicacid methyl ester hydrochloride as a tan foam (1.15 g), C₂₂H₂₃N₂O₃ClS:MH⁺ 431, from2-[3-{tert-butoxycarbonyl-[2R-(tert-butyidimethylsilanoxy)-2-(3-chlbrophenyl)ethyl]-amino}ethylamino)phenyl]thiophene-3-carboxylicacid methyl ester (1.65 g).

[0147] Intermediate 24

[0148]2-(4-{2R-[2-(3-Chlorophenyl)-2R-hydroxyl-ethylamino]propylamino}phenyl)thiophene-3-carboxylicacid methyl ester as an orange oil (0.060 g), C₂₃H₂₅N₂O₃ClS: MH⁺ 445,from2-[4-(2R-{tert-butoxycarbonyl-[2R-(tert-butyldimethylsilanoxy)-2-(3-chlorophenyl)ethyl]amino}propylamino)phenyl]thiophene-3-carboxylicacid methyl ester (0.155 g).

[0149] Intermediate 25

[0150] Methyl2-(3-{2R-[2-(3-chlorophenyl)-2R-hydroxyl-ethylamino]propylamino}phenyl)furan-3-carboxylateas a white foam (992 mg), C₃₄H₄₇N₂O₆SiCl: [MH⁺] 643, from2-(3-aminophenyl)furan-3-carboxylic acid methyl ester (700 mg) and{2R-(tert-butoxycarbonyl)-[2R-(tert-butyldimethylsilanoxy)-2-(3-chlorophenyl)ethyl]amino}propionaldehyde(1.26 g).

[0151] Intermediate 26

[0152] Methyl2-(3-{2R-[2-(3-chlorophenyl)-2R-hydroxyl-ethylamino]-N-ethylpropylamino}phenyl)furan-3-carboxylateas a white foam (331 mg), C₃₅H₅₁N₂O₆SiCl: [MH⁺] 671, from methyl2-(3-{2R-[2-(3-chlorophenyl)-2R-hydroxyl-ethylamino]propylamino}phenyl)furan-3-carboxylate(429 mg) and acetaldehyde (47 mg).

[0153] Intermediate 27

[0154] Ethyl 2-(3-aminophenyl)-3-furoate Hydrochloride

[0155] To a stirred solution of 1-bromo-3-nitrobenzene (50 g) and ethyl3-furoate (48.6 g) in toluene (500 mL) were added potassium acetate(36.4 g) and tetrakis(triphenylphosphine)palladium(0) (14.3 g). Themixture was heated at reflux for 66 hours, cooled to room temperature,and filtered through Celite (50 g). The filtercake was rinsed with ethylacetate (2×200 mL). The combined filtrate/rinse was concentrated to anoil. Methanol (500 mL) and 10% palladium on carbon (50% wet paste, 3.2g) were added. The mixture was stirred under an atmosphere of hydrogenuntil uptake ceased. The mixture was filtered through Celite (50 g), andthe filtercake was rinsed with ethyl acetate (200 mL). The combinedfiltrate/rinse was concentrated to an oil, and ethyl acetate (250 mL)was added. The solution was washed with water (100 mL). The organicphase was dried over sodium sulfate, filtered, and concentrated to anoil. Dichloromethane (50 mL) was added, and the resulting solution wasfiltered through a silica gel plug (100 g). The plug was rinsed withdichloromethane (2500 mL) to extract all ethyl2-(3-aminophenyl)-3-furoate hydrochloride. The combined filtrate/rinsewas concentrated to an oil, and methyl tert-butyl ether (250 mL) wasadded. To this stirred solution was slowly added 4.0 M HCl in dioxane(93 mL). After aging for 15 minutes at 0-5° C., the precipitate wascollected by filtration, washed with methyl tert-butyl ether (2×100 mL),and dried in vacuo at 45-50° C. to yield 46.8 g (71% th) of the titlecompound as a beige solid. 1H NMR (300 MHz, d6-DMSO) δ:7.90 (d, 1H),7.78 (m, 2H), 7.51 (t, 1H), 7.30 (d, 1H), 4.25 (q, 2H), 1.26 (t, 3H).

[0156] Intermediate 28

[0157] Ethyl2-[3-(2-methyl-4,5-dihydro-1H-imidazol-1-yl)phenyl]-3-furoate

[0158] N-(2-chloroethyl)acetamide (1.21 g) in ethyl acetate (10 mL) wasadded over 10 min to a stirred suspension of phosphorus pentachloride(2.08 g) in ethyl acetate (2 mL) at 0° C. under nitrogen to give a clearpale straw solution. After 45 min at 0° C. toluene (12 mL) was added,and ethyl 2-(3-aminophenyl)-3-furoate hydrochloride (1.78 g) was addedin one portion into the above solution at 0-5° C. The mixture wasstirred at 0-5° C. for 10 min and then allowed to warm up to 20° C.After 2 h formation of the amidine is essentially complete (HPLC ethyl2-(3-aminophenyl)-3-furoate hydrochloride <2% @ 220 nm, a/a). Themixture was cooled to 0-5° C., crushed ice (18 g) was added over 20 minto destroy phosphorus oxychloride. Ammonium hydroxide (28%, 6.49 mL) wasadded at a rate that the internal temperature was kept below 25° C. (ca.15 min). After 1 h at 20° C. additional ethyl acetate (12 mL) added tothe above mixture, the organic layer was separated, washed withdeionized water (2×1 2 mL), and concentrated under reduced pressure. Theresidue was dissolved in acetone (5 mL) and ethyl acetate (5 mL), andtreated with oxalic acid (0.72 g) at 40° C. for 30 min. After aging at<20° C. for at least 12 h, the precipitate was collected by filtration,washed with acetone (2×0.5 vol), and dried in vacuo at 45-50° C. toyield 1.9 g (73%) of white solid. ¹H NMR (400, d₆-DMSO) δ: 8.00 (s, 1H),7.92-7.90 (m, 2H), 7.64-7.55 (m, 2H), 6.90 (d, 1H), 4.32 (t, 2H), 4.22(q, 2H), 3.93 (t, 2H), 2.22 (s, 3H), 1.24 (t, 3H).

EXAMPLE 1

[0159]2-(3-{2R-[2-(3-Chlorophenyl)-2R-hydroxyl-ethylamino]propylamino}pheny)furan-3-carboxylicAcid

[0160] To a solution of2-(3-{2R-[2-(3-chlorophenyl)-2R-hydroxyl-ethylamino]propylamino}phenyl)furan-3-carboxylicacid methyl ester (0.19 g) in 3:1 methanol: water (5.5 mL) was addedsolid lithium hydroxide monohydrate (0.185 g). The solution was stirredat room temperature for 18 h and concentrated at reduced pressure. Theresidue was chromatographed on silica eluting with chloroform: m thanol:conc. ammonium hydroxide (10:5:1) to give the title compound as a tansolid (0.067 g). m.p.=184-186° C., HPLC system 1: t_(R) 11.19 min.

[0161] Similarly Prepared Were:

EXAMPLE 2

[0162]2-(3-{[2-(3-Chlorophenyl)-2R-hydroxyl-ethylamino]ethylamino}phenyl)furan-3-carboxylic acid as a white solid (317 mg), m.p.=250° C. (dec),C₂₁H₂₁N₂O₄Cl: [MH⁺] 402. Assay Found C 62.65; H 5.21; N 6.91%,C₂₁H₂₁N₂O₄Cl₁ requires C 62.92; H 5.28; N 6.99%, from2-(3-{2R-[2-(3-chlorophenyl)-2R-hydroxyl-ethylamino]propylamino}phenyl)furan-3-carboxylicacid methyl ester hydrochloride (613 mg).

[0163] In an alternative preparation, ammonium hydroxide (28%, 13 mL)was added over 10 min to a mixture of ethyl2-[3-(2-methyl-4,5-dihydro-1H-imidazol-1-yl)phenyl]-3-furoate (13.0 g),deionized water (104 mL), and toluene (104 mL). After 30 min stirring,the organic layer was collected, washed with deionized water (26 mL),and concentrated to ca. 30 mL to remove traces of water azetropically.(R)-3-Chlorostyrene oxide (5.17 g) was added, and the resultant washeated under nitrogen at 110 C. for at least 14 h. The mixture wascooled to ca. 50° C. 1M Sodium hydroxide aqueous solution (77.8 mL) andmethanol (39 mL) were added, and the apparatus was configured fordistillation. After ca. 1 h, the homogeneous solution obtained washeated at reflux (ca. 4 h) until the hydrolysis was complete (HPLCacetate <2% @ 220 nm, a/a). The mixture was cooled to <50° C.

[0164] Methanol (26 mL) and 1M hydrochloric acid (78 mL) were heated toca. 50° C. The reaction mixture from above was added over 20 min, andthe resultant slurry was cooled to <20° C. and aged for a further 30min. The product was collected by filtration, washed with deionizedwater (2×26 mL), and dried in vacuo at 50° C. to yield 12.7 g (95%) ofthe title compound as an off-white solid.

EXAMPLE 3

[0165]2-(4-{2R-[2-(3-Chlorophenyl)-2R-hydroxylethylamino]propylamino}phenyl)furan-3-carboxylicacid as a tan solid (0.059 g), HRMS C₂₂H₂₃N₂O₄Cl: MH⁺ calc 415.1425,found 415.1412 Δ=1.3 mmu, HPLC system 1: t_(R) 11.06 min., from2-(4-{2R-[2-(3-chlorophenyl)-2R-hydroxylethylamino]propylaminophenyl}furan-3-carboxylicacid methyl ester (0.19 g).

EXAMPLE 4

[0166]2-(3-{2R-[2-(3-Chlorophenyl)-2R-hydroxyl-ethylamino]propylamino}phenyl)thiophene-3-carboxylicacid as a tan solid (0.088 g), HRMS C₂₂H₂₃N₂O₃ClS MH⁺ calc 431.1196,found 431.1180 Δ=1.6 mmu, HPLC system 1: t_(R) 12.38 min., from2-(3-{2R-[2-(3-chlorophenyl)-2R-hydroxyl-ethylamino]propylamino}phenyl)thiophene-3-carboxylicacid methyl ester (0.086 g).

EXAMPLE 5

[0167]2-(3-{[2-(3-Chlorophenyl)-2R-hydroxyl-ethylamino]ethylamino}phenyl)thiophene-3-carboxylicacid as a cream colored solid (296.8 mg), m.p.=275° C. (dec)C₂₁H₂₁N₂O₃ClS: [MH⁺] 417. Assay Found C 60.47; H 5.04; N 6.67%,C₂₁H₂₁N₂O₄Cl₁ requires C 60.50; H 5.08; N 6.72%, from2-(3-{2R-[2-(3-chlorophenyl)-2R-hydroxyl-ethylamino]propylamino}phenyl)thiophene-3-carboxylicacid methyl ester hydrochloride (1.15 g).

EXAMPLE 6

[0168]2-(4-{2R-[2-(3-Chlorophenyl)-2R-hydroxyl-ethylamino]propylamino}phenyl)thiophene-3-carboxylicacid as a tan solid (0.010 g), HRMS C₂₂H₂₃N₂O₃ClS MH⁺ calc 431.1196,found 431.1183 Δ=1.3 mmu, HPLC system 1: t_(R) 12.03 min., from2-(4-{2R-[2-(3-chlorophenyl)-2R-hydroxyl-ethylamino]propylamino}phenyl)thiophene-3-carboxylicacid methyl ester (0.060 g).

1. A compound of formula (I), or a pharmaceutically acceptablederivative thereof.

wherein X is oxygen or sulfur, optionally substituted by one or moregroups selected from C₁₋₄ alkyl and halogen, and where the heterocyclecontaining X is substituted meta or para to the depicted NH; R¹ ishydrogen or C₁₋₆alkyl; R represents substituents selected fromC₁₋₆alkyl, halogen, trifluoromethyl, and C₁₋₆alkoxy; and n represents aninteger from 0-4.
 2. A compound of claim 1 wherein said compound is anagonist for human beta-3 adrenoceptor.
 3. A compound of claim 1 whereinsaid compound is a selective agonist for human beta-3 adrenoceptor.
 4. Acompound of claim 1 wherein the heterocycle containing X is substitutedmeta to the depicted NH.
 5. A compound of claim 1 wherein R¹ is hydrogenor methyl.
 6. A compound of claim 1 wherein when R¹ is other thanhydrogen, the stereochemisty around the carbon to which R¹ is bonded, isR.
 7. A compound of claim 1 wherein R is chlorine, fluorine, or CF₃. 8.A compound of claim 1 wherein n is 0, 1, or
 2. 9. A compound of claim 1wherein n is
 0. 10. A compound of claim 1 wherein the stereochemistyaround the carbon to which the depicted OH is bonded, is R.
 11. Acompound of claim 1 wherein said compound is selected from the groupconsisting of2-(3-{2R-[2-(3-Chlorophenyl)-2R-hydroxyl-ethylamino]propylamino}phenyl)furan-3-carboxylicacid;2-(3-{[2-(3-Chlorophenyl)-2R-hydroxyl-ethylamino]ethylamino}phenyl)furan-3-carboxylicacid;2-(4-{2R-[2-(3-Chlorophenyl)-2R-hydroxylethylamino]propylamino}phenyl)furan-3-carboxylicacid;2-(3-{2R-[2-(3-Chlorophenyl)-2R-hydroxyl-ethylamino]propylamino}phenyl)thiophene-3-carboxylicacid;2-(3-{[2-(3-Chlorophenyl)-2R-hydroxyl-ethylamino]ethylamino}phenyl)thiophene-3-carboxylicacid;2-(4-{2R-[2-(3-Chlorophenyl)-2R-hydroxyl-ethylamino]propylamino}phenyl)thiophene-3-carboxylicacid; and pharmaceutically acceptable derivatives thereof.
 12. Acompound of claim 1 wherein said compound is selected from the groupconsisting of2-(3-{[2-(3-Chlorophenyl)-2R-hydroxyl-ethylamino]ethylamino}phenyl)furan-3-carboxylicacid;2-(3-{[2-(3-Chlorophenyl)-2R-hydroxyl-ethylamino]ethylamino}phenyl)thiophene-3-carboxylicacid; and pharmaceutically acceptable derivatives thereof.
 13. Apharmaceutical formulation comprising a compound of claim
 1. 14. Acompound according to any one of claims 1 to 12 for use in therapy. 15.Use of a compound according to any one of claims 1 to 12 in themanufacture of a medicament for the treatment of a mammal, includingman, of conditions or diseases susceptible of amelioration by an atypical beta-adrenoceptor agonist.
 16. Use of a compound according toclaim 15 wherein said condition or disease is obesity.
 17. A method forthe prevention or treatment of clinical conditions or diseasessusceptible to amelioration by administration of an a typicalbeta-adrenoceptor agonist, comprising administration of an effectiveamount of a compound of claim
 1. 18. The method of claim 17 wherein saidcondition or disease is obesity.